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WO2008015475A1 - Gels destinés à être utilisés dans le contrôle de plaies - Google Patents

Gels destinés à être utilisés dans le contrôle de plaies Download PDF

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Publication number
WO2008015475A1
WO2008015475A1 PCT/GB2007/050454 GB2007050454W WO2008015475A1 WO 2008015475 A1 WO2008015475 A1 WO 2008015475A1 GB 2007050454 W GB2007050454 W GB 2007050454W WO 2008015475 A1 WO2008015475 A1 WO 2008015475A1
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WIPO (PCT)
Prior art keywords
gel
molecules
wound
albumin
polysaccharide
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PCT/GB2007/050454
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English (en)
Inventor
Roy Harris
Wael Nasi
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Advanced Protein Systems Limited
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Publication of WO2008015475A1 publication Critical patent/WO2008015475A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/06—Pectin; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/225—Mixtures of macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/44—Medicaments
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L89/00—Compositions of proteins; Compositions of derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/41—Anti-inflammatory agents, e.g. NSAIDs

Definitions

  • This invention relates to the field of wound care, and in particular to the formation of gels suitable for topical administration as wound dressings.
  • the major characteristics of a dressing that determine its suitability for application to a particular type of wound include its conformability to the body (desirable to maintain complete wound closure), fluid- and odour-absorbing characteristics, handling and adhesive properties, and the presence of antibacterial and haemostatic activity where appropriate. Other factors which may influence product selection include the potential for the dressing to cause sensitivity reactions, the ease of application and removal (important in minimising pain and trauma to the wound surface) and the interval between dressing changes.
  • Dressings should not shed particles or fibres that may delay healing or predispose the wound to infection. They should also not contain extractables that may have an adverse effect on cell growth. It is usually desirable for a wound to heal as quickly as possible, but without scarring.
  • wound care dressing Numerous types of wound care dressing are available. Among those that are most commonly used are hydrogels, hydrocolloids, alginates, polymer films and polymer foams. Each product type has general characteristics but the construction and therefore performance of different brands may vary considerably within a particular product type. No single product is suitable for use in all wound types or at all stages of healing.
  • Hydrogel wound dressings are particularly useful for burns, ulcers and deep wounds such as pressure sores because, amongst other things, they soothe pain, give a cooling sensation and provide control of wound surface hydration. Unlike many alginate dressings, for example, they do not stick to the wound and can be removed easily without pre-soaking.
  • wound dressings that provide the benefits of hydrogel dressings, but have additional desirable characteristics and thereby afford superior wound healing, would clearly be advantageous.
  • wound dressings that also deliver active ingredients, eg drugs, to the wound site in a controlled manner would be of additional benefit.
  • Desirable active ingredients may help to fight or protect against infection, reduce pain, reduce inflammation and/or facilitate healing, eg by encouraging clotting.
  • HSA Human serum albumin
  • HSA Human serum albumin
  • HSA may offer a controlled release mechanism for drug delivery.
  • HSA binds metal ions (eg zinc, copper and silver), which may be important in the anti-infective treatment of wounds, and may detoxify the wound site and scavenge free radicals.
  • Pathological platelet aggregation is inhibited by HSA, and inflammatory chemical levels (and therefore itching) are also decreased.
  • HSA is non-allergenic and may naturally confer antibacterial or antiviral activity at the wound site.
  • Albumin is currently employed for a number of other medical uses, eg to increase blood volume.
  • WO 99/66964 relates to albumin-based compositions for use as bioadhesives, surgical sealants, and implantable devices for drug delivery and prosthesis.
  • the adhesive properties of these compositions make them unsuitable for use as external wound dressings and, although the compositions are intended to break down in the body, suitability for internal use is also limited by unwanted adhesion. Following surgical procedures, an adhesive intended to re-join damaged tissue may also attach the wound site to adjacent tissues/organs and cause further damage.
  • WO 99/66964 discloses the use of accessory molecules to alter the rate and/or degree of cross-linking between albumin molecules. It is stated that dicarboxylic acids are able to accelerate the gelation of bovine serum albumin. However, we have found that products formed in accordance with WO99/66964 are rather dry and brittle. Such brittle products are unsuitable for use as wound dressings.
  • a method of forming a wound dressing which method comprises forming a protein polymer by reacting a protein with a polyfunctional spacer, or an activated derivative thereof.
  • Preferred spacers are dicarboxylic acids, more preferably alkylene dicarboxylic acids.
  • Wound dressings for the management of chronic wounds may be prepared by cross-linking HSA with adipic acid to produce gel pads.
  • the protein polymers formed by reacting a protein with an alkylene dicarboxylic acid, or an activated derivative thereof are suitable for a number of other therapeutic applications.
  • the chemistry is simple, yet a wide range of protein polymer systems may be prepared by adjustment of only a small number of variables and, as well as promoting a high degree of control, the properties of the polymers can be predicted reasonably well from the composition and reaction conditions.
  • the ability to prepare protein polymer products with such a wide range of properties and uses is highly desirable, and the polymers disclosed in WO 2005/079877 present clear advantages over the prior art.
  • a gel comprising a cross-linked matrix of albumin molecules and polysaccharide molecules, which polysaccharide molecules have appendant groups that are carboxyl groups or activated derivatives or salts thereof.
  • a method of forming a gel comprises reacting albumin with a polysaccharide having appendant groups that are carboxyl groups or activated derivatives or salts thereof.
  • a wound dressing including a gel comprising a cross-linked matrix of albumin molecules and polysaccharide molecules, which polysaccharide molecules have appendant groups that are carboxyl groups or activated derivatives or salts thereof.
  • Albumins that may be used as in the present invention may be human or animal, eg mammalian albumin.
  • the albumin used is preferably of human origin, ie actually derived from humans, or is identical (or substantially so) in structure to albumin of human origin.
  • a particularly preferred albumin is thus human serum albumin.
  • Human serum albumin may be serum-derived, for instance obtained from donated blood. Human serum albumin is readily available as a fractionated blood product and has been safely used for many years for intravenous delivery as a blood expander.
  • the albumin eg human serum albumin
  • the albumin may be a recombinant product derived from microorganisms (including cell lines), transgenic plants or animals that have been transformed or transfected to express the protein.
  • Suitable forms of rHA may be obtained commercially from Novozymes Delta Ltd, Nottingham, United Kingdom.
  • non-human albumin may be used.
  • albumins may be recombinant products, but will more commonly be animal- derived. Examples of such albumins include bovine serum albumin, horse serum albumin, dog serum albumin etc. Animal albumins may be useful in, for instance, veterinary applications of the wound dressing of the invention.
  • Functional groups present on albumin that will react with the carboxyl groups on the polysaccharide include amino groups.
  • amino groups on the albumin will react with the appendant carboxyl groups on the polysaccharide to form amide bonds.
  • Polysaccharides having appendant groups that are carboxyl groups or activated derivatives or salts thereof, for use in the present invention may be naturally-occurring (including functionalised derivatives of naturally-occurring polysaccharides) or synthetic.
  • the most preferred polysaccharides are pectins, which are naturally- occurring polysaccharides that contain appendant carboxyl groups or derivatives thereof.
  • Pectins are complex polysaccharides consisting mainly of esterifed D-galacturonic acid residues in an ⁇ -(1 -4) chain.
  • the acid groups along the chain are largely estehfied with methoxy groups in the natural product.
  • the free hydroxyl groups can also be acetylated.
  • the galacturonic acid main chain has the occasional rhamnose group present which disrupts the chain helix formation.
  • Pectins are also known to contain other neutral sugars which are present in the side chains.
  • the most common side chain sugars are xylose, galactose and arabinose.
  • the side chains tend to occur in groups and have led to the description of the pectin molecule as having "hairy" regions (with side chains) and "smooth" regions (with few or no side chains).
  • pectins are categorised according to their methoxy content and whether they form gels quickly or slowly. Generally, pectins can be split into high methyl ester (HM) pectins (>50% estehfied) and low methyl ester (LM) pectins ( ⁇ 50% esterified). Low methyl ester pectins can also be aminated.
  • HM high methyl ester
  • LM low methyl ester pectins
  • Low methyl ester pectins can also be aminated.
  • Pectin as extracted normally has more than 50% of the acid units esterified, and is therefore an HM pectin.
  • High methyl ester pectins are classified in groups according to their gelling temperature as rapid-set to slow-set pectins.
  • pectin Modification of the extraction process, or continued acid treatment, will yield LM pectin. Some pectins are treated during manufacture with ammonia to produce amidated pectins, which have particular advantages in some applications.
  • the general term "pectin”, as used in the context of the present invention includes pectin, LM pectin ( ⁇ 50% methylated), HM pectin (>50% methylated), de-estehfied pectin (wherein one or more methyl ester groups have been removed from the pectin molecules), pectin acid (polygalacturonic acids that are essentially free from methyl ester groups), pectinic acid (polygalacturonic acids with a low number of methyl ester groups), and pectates / pectinates (normal or acid salts).
  • pectin impart several advantageous properties to the wound dressings of the present invention.
  • Pectin has been shown to protect growth factors and thus accelerate wound healing.
  • Pectin reduces inflammation and reduces effects of arthritis by maintaining the elasticity of connective tissue in the joints thus allowing them to move smoothly. A similar effect is exerted on collagen in wound repair, allowing the improvement of the remodelling state of healing, and leading to faster healing of chronic wounds with reduced scarring.
  • Pectin also has the ability to regulate cell uniformity. It is an active ingredient in aloe vera preparations that are used as topical ointments in wound management. As a wound heals, the cells around it are stimulated by growth factors to divide and grow into the wound. When aloe pectin is added to the wound, it serves as a binding agent, welding growth factors together and thus protecting them from degradation. If pectin alone is applied to a wound, it is thought to form a soft gel that binds the growth factors and makes them persist for much longer, thus producing a significant acceleration of wound healing. A major benefit of the use of pectin is its ability to bind water, and thus to remove or control exudates in chronic wounds.
  • albumin- based gel polymers made with adipic acid as a coupling agent are described in WO 2005/079877. These gels contain -80% water and can absorb a further -60% of their weight with additional water ( ⁇ 1.5 x weight).
  • pectin with albumin to form a gel according to the present invention, it is possible to increase the water uptake several-fold whilst maintaining the therapeutic and physical properties of the gel.
  • This factor can be further enhanced by producing albumin-pectin gel foams (sponge-like gels that retain their integrity when fully saturated). This is important in wound exudate control and could also be an important factor in the treatment of burns or dry wounds.
  • gel foams provide improved means of loading and releasing drugs, eg antibiotics, pain relievers and/or tissue repair factors at the site of action.
  • Gels according to the invention may be capable of absorbing amounts of water in excess of 100% of the weight of the gel, or in excess of 120%, or in excess of 140%, or in excess of 160%.
  • the method of forming the gel according to the invention most preferably comprises mixing a solution of the albumin molecules with a solution of the polysaccharide molecules. This may involve adding a solution of the albumin molecules to a solution of the polysaccharide molecules, or vice versa.
  • the molar ratio of albumin molecules to polysaccharide molecules should be greater than 1 :1 , and more preferably greater than 10:1 , eg greater than 15:1 or greater than 20:1.
  • the concentration of albumin molecules in the gel according to the invention may be greater than 50 mg/ml, or greater than 100 mg/ml, and less than 500 mg/ml, or less than 250 or 200 mg/ml.
  • the concentration of albumin molecules may be in the range 50 to 500 mg/ml, more commonly 50 to 250 mg/ml, or 100 to 200 mg/ml.
  • the concentration of polysaccharide molecules in the gel according to the invention may be greater than 1 mg/ml, or greater than 2 mg/ml, and less than 20 mg/ml, or less than 15 mg/ml.
  • the concentration of polysaccharide molecules may be in the range 1 to 20 mg/ml, more commonly 2 to 15 mg/ml.
  • the appendant carboxyl groups on the polysaccharide may have the form of carboxylic acid (-COOH) groups, or some or all of the carboxyl groups may be in the form of salts (carboxylates) or esters or other derivatives. References herein to carboxyl groups should be understood to encompass all these possibilities.
  • the formation of the gel according to the invention will generally involve the formation of covalent bonds between the appendant carboxyl groups of the polysaccharide molecules and functional groups in the albumin molecules.
  • covalent bonds may be formed between the carboxyl groups and amino groups present in the albumin molecules. It should be understood, however, that other forms of covalent bond may also be formed, including covalent bonds between albumin molecules as well as between albumin molecules and polysaccharide molecules.
  • the carboxyl groups In order to facilitate reaction of the polysaccharide with the albumin, it will generally be desirable for the carboxyl groups to be activated, ie for at least some of the carboxyl groups to be converted to groups of greater reactivity towards groups in the protein. Suitable activation chemistries will be familiar to those skilled in the art, and include the formation of active ester groups.
  • activators are carbodiimide compounds, and a particularly preferred activator for use in the invention is 1 -ethyl-3- (dimethylaminopropyl)-carbodiimide (EDC).
  • EDC 1 -ethyl-3- (dimethylaminopropyl)-carbodiimide
  • the polysaccharide is added to an albumin solution.
  • An activator eg EDC, is added to the mixture and the reaction is allowed to proceed.
  • the concentration of the albumin solution, the ratio of carboxyl groups on the polysaccharide, the amount of activator and the reaction time are all important to the desired result.
  • the activator reacts with the carboxyl groups to produce a derivative which is more reactive towards nucleophiles, hence promoting reaction with the available NH 2 groups on the albumin.
  • the efficiency of the EDC-mediated crosslinking reaction can be increased by the addition of N-hydroxysuccinimide (NHS) or a derivative of it such as N- hydroxy sulphosuccinimide (sulpho-NHS) which is more water soluble.
  • NHS N-hydroxysuccinimide
  • sulpho-NHS N- hydroxy sulphosuccinimide
  • the properties of the gels can be varied from very sticky to soft but non-adhesive, and the hardness can be increased up to very hard gels with low deformation and high compressibility.
  • the properties of the gels will control the amount of water absorbed or lost .
  • the nature of the gel will also regulate the rate of degradation in the presence of proteases as found in the exudates of chronic wounds.
  • Proteases are a family of proteolytic enzymes that play a critical role in the various phases of wound repair at the cellular level. Proteases for example, will assist in revascularisation of the wound during angiogenesis, assist in debridement and cleansing of the wound of necrotic tissue, foreign bodies and bacteria and digest the extracellular matrix and assist in tissue remodeling. Proteases regulate the balance between tissue synthesis and tissue degradation. By appropriate choice of parameters, it may be possible to form gels that do not degrade totally when applied to a wound site, thereby facilitating wound management and easy removal of the dressing.
  • Parameters that can be varied to achieve these differing results include the choice of albumin, the choice of polysaccharide, the concentrations of the reactants, the reaction pH, temperature and duration of the various reaction steps.
  • Gels according to the invention may retain their integrity after application to a wound, such that the gel may be removed from the wound in substantially intact form, even after a period of application to the wound in excess of 1 , 2, 3 or 4 days.
  • the speed of gel formation can also be varied over a wide range by controlling the ratio of reagents used to form the gel, the pH and the temperature.
  • the wound dressings of the present invention may take the form of bandages impregnated with the gel, gel sheets, either with or without a supporting substrate, or three-dimensional articles. Gels of particular shapes and sizes may be specifically moulded for particular wound types or body areas. Alternatively, appropriately sized dressings may be cut to size from larger gel sheets immediately before application.
  • a wound dressing may be desirable for a wound dressing to deliver therapeutically active ingredients to the wound site.
  • Drugs such as antibiotics, antivirals, antiinflammatory agents, haemostatic agents, pain killers and phages may be added to the composition directly or via carriers that promote absorption from the wound site, eg liposomes.
  • Actives that promote or improve tissue repair may also be incorporated, eg growth factors, anti-scarring agents, and agents that promote angiogenesis.
  • wound odour may be reduced or removed by incorporating into the dressing one or more agents (eg charcoal) which absorb the volatile molecules that are responsible for the smell.
  • a method for the treatment of a wound comprises the topical application to the wound of a wound dressing including a gel comprising a cross-linked matrix of albumin molecules and polysaccharide molecules, which polysaccharide molecules have appendant groups that are carboxyl groups or activated derivatives or salts thereof, wherein the gel comprises one or more therapeutically active agents.
  • the incorporated active compounds will be delivered to the wound site by leaching from the gel and by release from the gel as it degrades.
  • a key factor in determining the rate of release of an active will be the softness/hardness of the gel. Active compounds will leach out of softer gels more easily because they are not held as effectively by the cross-linked albumin and polysaccharide molecules. Softer polymers will also break down at a faster rate because the looser structure will allow moisture and enzymes to penetrate more easily.
  • foamed gels sponge-like gels that retain their integrity when fully saturated
  • Particular classes of therapeutic agent that may be incorporated into the wound dressings of the present invention include antibiotics, antiinflammatories and pain killers.
  • Free radical scavengers and antioxidants eg vitamin C, vitamin E, polyphenols
  • antioxidants eg vitamin C, vitamin E, polyphenols
  • Antibiotics may be given systemically, ie orally (pills and capsules) or by injection, or topically.
  • topical antibiotics such as Neomycin, bacitracin and polymixin seem to interfere with new skin cell formation.
  • the antibiotics are included in wound dressings in order to reduce any negative effect on tissue repair, whilst maintaining efficacious levels of the antibiotic.
  • Human serum albumin is a natural binder of certain drugs, including aspirin, ibuprofen and other anti-inflammatory drugs.
  • the wound management properties of the gel may therefore be enhanced by the addition of pain killers such as ibuprofen, codeine, morphine etc or by the addition of anaesthetics such as lidocaine.
  • albumin and pectin both naturally bind copper and have the ability to traverse membranes and target cells to deliver copper ions in a safe and efficient manner. Consequently, albumin-pectin gels, according to the present invention, provide an ideal delivery system for copper ions.
  • Copper has long been known to be an antimicrobial agent and an essential co-factor in many processes including cell mobility and proliferation, matrix remodelling enzymes and angiogenesis.
  • copper is effective against MRSA (methicillin-resistant Staphylococcus aureus), Helicobacter (a major cause of gastric ulcers that can often lead to cancerous growths if not treated), and other pathogens.
  • Bacteria do not become resistant to copper, as is the case with silver, and copper is less toxic than other heavy metal ions.
  • Copper is a natural metal ion in the body (again unlike silver), and it is central to a number of processes involved in wound healing, including the reduction of tissue oxidative damage and activation of remodelling, the stimulation of angiogenesis by induction of growth factors, the control of copper-dependent enzymes (eg lysyl oxidase) that are important in matrix remodelling, and antiscarhng.
  • processes involved in wound healing including the reduction of tissue oxidative damage and activation of remodelling, the stimulation of angiogenesis by induction of growth factors, the control of copper-dependent enzymes (eg lysyl oxidase) that are important in matrix remodelling, and antiscarhng.
  • copper complexes such as copper aspirinate and copper tryptophanate markedly increase the healing rate of ulcers and wounds. For example, copper complexes heal gastric ulcers five days sooner than other reagents. Further, it has been shown that, whereas non-steroidal anti-inflammatory drugs, such as ibuprofen and enefenamic acid suppress wound healing, copper complexes of these drugs promote normal wound healing while at the same time retaining antiinflammatory activity.
  • copper has an important role to play in the prevention or moderation of certain neurodegenerative diseases including the polyglutamine diseases (such as Friedreich's ataxia and Huntington's Disease), Parkinson's Disease, Wilson's and Menkes' Diseases, amyotrophic lateral sclerosis (Lou Gehrig's Disease, also called “Motor Neurone Disease” in the UK), and Alzheimer's Disease. It has recently been suggested that copper also affects the class of ailments known as “prion diseases”.
  • BSE bovine spongiform encephalopathy
  • CWD chronic wasting disease
  • FSE feline spongiform encephalopathy
  • CJD Creutzfeldt- Jakob Disease
  • TSEs transmissible spongiform encephalopathy diseases
  • the term "spongiform” refers to the porous nature of respective characteristic microscopic vacuoles that form in the brains of afflicted animals or humans. The appearance of this vacuolation differs between the animal and the human disease; however, both have sponge-like aspects.
  • Prions are classified as "proteinaceous infectious particles" which are infectious agents in that they are capable of self-replication, contain no nucleic acid (DNA or RNA), invoke no immune response, and can change into an abnormal form that causes prion diseases.
  • the mechanism proposed for the occurrence of these conditions is that the normal prion protein (PrP) is converted into an abnormal or “rogue” form, PrP Sc , with an altered conformation.
  • prion protein selectively binds copper (II) ions.
  • the PrP Sc infectious isoform is derived from PrP in a conversion reaction that involves a dramatic structural reorganization of the protein.
  • the binding of 2- 4 copper (II) ions promotes a shift from a beta-sheet structure (PrP Sc ) to a predominantly alpha-helical structure (PrP). Copper is the controlling factor in forming and maintaining the normal (non-infective) form of PrP.
  • Figure 1 shows the effect of pectin concentration on gelling time (as described in Example 2).
  • Figure 2 shows the effect of pectin concentration on the water absorption properties of the gel (as described in Example 2).
  • Figure 3 shows the effect of HSA concentration on the gelling time using 1 % citrus pectin >60% estehfied (as described in Example 3).
  • Figure 4 shows the effect of HSA concentration on the water absorption potential of the gel, again using 1 % citrus pectin >60% esterified (as described in Example 3).
  • Figure 5 shows the effect of EDC concentration on gelling using 1 % citrus pectin >60% esterified (as described in Example 4).
  • Figure 6 shows the effect of EDC concentration on the water absorption potential of the gel, again using 1 % citrus pectin >60% esterified (as described in Example 4).
  • Figure 7 shows the effect of the gelling solution pH on the gelling time (as described in Example 5).
  • Figure 8 shows the release of copper from gels with time (as described in
  • FIG. 9 shows the variation in release of copper with pH (as described in
  • Gels according to the invention were prepared by cross-linking human serum albumin and pectin with EDC.
  • the gelling solution was prepared by dissolving the required amount of pectin in 20% HSA solution (Grifols). The pH of the resulting solution was measured and the gelling reaction was continued by the addition of EDC dissolved in water.
  • pectin is dissolved in the required amount of water and 20% HSA solution is added to this to give the required concentrations of both components.
  • the gelling time was determined as the time it took for the HSA/pectin/EDC solution to set as a gel.
  • the pH of the gel was determined after at least one day by suspending the gel in water (eg 1 ml of gel in 10mI water).
  • the percentage of the water absorbed was measured by weighing the gel before and after suspension in water (eg 1 ml gl in 10ml water) for different time periods.
  • the character of the gels can be qualitatively assessed on the basis of appearance, flexibility and robustness, hardness or degree of gelling. In the examples below information is given in individual tables using the following numbering system: 0 No gel or viscous solution
  • Example 1 The type and the source of the pectin used
  • pectin was tested in the production of the gels. The main difference, apart from the source of material, was the degree of estehfication.
  • the pectin (1 %) was dissolved in 20% HSA solution and the pH adjusted to pH6.5-6.6 by the addition of either dilute NaOH or HCI.
  • EDC was dissolved in water and added to HSA/pectin solution to give a molar ratio of 1 :33.5 (HSA:EDC).
  • the final concentration of HSA was 160mg/ml.
  • 1 ml gel contained 160mg HSA, 8mg pectin and 15.4mg EDC.
  • the EDC concentration in the gel has a great effect on the gel properties. This was determined by reacting a fixed volume of gelling solution with constant concentrations of HSA and pectin ( 1% citrus pectin >60% esterified (H&F CU401 USP) in 20% Grifols HSA (pH 6.45)) with a varying amount of EDC. Table 4: Effect of EDC concentration on the gel properties
  • Figures 5 and 6 show the effect of EDC concentration on the gelling time and percentage of water absorbed respectively.
  • the citrus pectin (Sigma) concentration was maintained at 1 %, HSA at 160mg/ml and the molar ratio of HSA:EDC at 1 :33.5. Percentage water uptake was measured after 24 hours. The pH was adjusted by addition of dilute HCI/NaOH as required.
  • the gelling reaction was monitored at three different temperatures (23 °C, 40 °C and 55 °C), keeping all the other variables constant (HSA:EDC 1 :33.5, HSA concentration 160mg/ml and pectin concentration 8mg/ml).
  • Example 8 The effect of charcoal on gel properties and odour control
  • Experiment 3 Effect of protease activity on release of copper from gels
  • Gels were prepared as in Experiment 1 above, containing 0.75mg copper per gram of gel.
  • the gels ( ⁇ 2.5cmx1.25cm) were placed in 10ml phosphate buffer saline / 0.1 mM calcium acetate containing 0, 0.5, 2, 5 or 15 units of elastase (protease found in chronic wounds) respectively. Aliquots were taken from each gel sample at 6, 24 and 48 hours and assayed for copper using the BC assay method.
  • 2-phospho-L-ascorbic acid salt (0.35%w/v) was added to a 1 %(w/v) pectin in 20% HSA solution.
  • EDC was added at a molar ratio of 1 :40 (HSA:EDC).
  • the resulting gel was a medium-soft flexible gel.
  • a 2ml 1 %w/v pectin/HSA (20%w/v) solution was prepared with vigorous stirring at room temperature. The solution became creamy white after 30 minutes, at which time 34.5 mg EDC (HSA/EDC molar ratio 1/30) in 0.5ml distilled water was added to the HSA/pectin solution with continued vigorous stirring for a further 12 minutes. The solution was then poured into a well and allowed to gel for one hour. The resulting gel was spongy in texture, white and flexible. The gel was placed in water for 24 hours and the water uptake of 172% was measured. This is a much higher percentage increase than is found with the standard gel at this level of crosslinking.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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Abstract

La présente invention concerne un gel comportant une matrice réticulée de molécules d'albumine et de molécules de polysaccharides ayant des groupes pendants qui sont des groupes carboxyles ou leurs dérivés ou sels activés. L'albumen est de préférence de l'albumine sérique humaine, avantageusement sous la forme d'un produit recombinant. Les molécules de polysaccharides sont de préférence des molécules de pectine. Les gels sont utiles pour une administration topique en tant que pansements de plaies.
PCT/GB2007/050454 2006-08-03 2007-07-27 Gels destinés à être utilisés dans le contrôle de plaies WO2008015475A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0615377A GB0615377D0 (en) 2006-08-03 2006-08-03 Gels for use in wound management
GB0615377.9 2006-08-03

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WO2008015475A1 true WO2008015475A1 (fr) 2008-02-07

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012103347A1 (fr) * 2011-01-26 2012-08-02 Whitson Stanley William Échafaudage biologique à base d'hydrogel et revêtement pour la restauration osseuse et dentaire
US20200261614A1 (en) * 2019-02-19 2020-08-20 Tc1 Llc Vascular graft and methods for sealing a vascular graft

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999066964A1 (fr) * 1998-06-23 1999-12-29 Surgical Sealants, Incorporated Albumine reticulee de carbodiimide pour bioadhesifs chirurgicaux de scellement et dispositifs a implanter
US20020022588A1 (en) * 1998-06-23 2002-02-21 James Wilkie Methods and compositions for sealing tissue leaks
GB2405343A (en) * 2003-08-29 2005-03-02 Johnson & Johnson Medical Ltd Charcoal Wound Dressings
WO2005079877A1 (fr) * 2004-02-17 2005-09-01 Advanced Protein Systems Limited Pansements comprenant un polymere proteique et un espaceur polyfonctionnel

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999066964A1 (fr) * 1998-06-23 1999-12-29 Surgical Sealants, Incorporated Albumine reticulee de carbodiimide pour bioadhesifs chirurgicaux de scellement et dispositifs a implanter
US20020022588A1 (en) * 1998-06-23 2002-02-21 James Wilkie Methods and compositions for sealing tissue leaks
GB2405343A (en) * 2003-08-29 2005-03-02 Johnson & Johnson Medical Ltd Charcoal Wound Dressings
WO2005079877A1 (fr) * 2004-02-17 2005-09-01 Advanced Protein Systems Limited Pansements comprenant un polymere proteique et un espaceur polyfonctionnel

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012103347A1 (fr) * 2011-01-26 2012-08-02 Whitson Stanley William Échafaudage biologique à base d'hydrogel et revêtement pour la restauration osseuse et dentaire
US8454980B2 (en) 2011-01-26 2013-06-04 Stanley William Whitson Hydrogel bioscaffold and coating for bone and tooth repair
US20200261614A1 (en) * 2019-02-19 2020-08-20 Tc1 Llc Vascular graft and methods for sealing a vascular graft

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